Title: Fibrostenotic eosinophilic esophagitis might reflect epithelial lysyl oxidase induction by fibroblast-derived TNF-α.
Authors: Kasagi, Yuta; Dods, Kara; Wang, Joshua X; Chandramouleeswaran, Prasanna M; Benitez, Alain J; Gambanga, Fiona; Kluger, Jonathan; Ashorobi, Tokunbo; Gross, Jonathan; Tobias, John W; Klein-Szanto, Andres J; Spergel, Jonathan M; Cianferoni, Antonella; Falk, Gary W; Whelan, Kelly A; Nakagawa, Hiroshi; Muir, Amanda B
Published In J Allergy Clin Immunol, (2019 07)
Abstract: BACKGROUND: Fibrosis and stricture are major comorbidities in patients with eosinophilic esophagitis (EoE). Lysyl oxidase (LOX), a collagen cross-linking enzyme, has not been investigated in the context of EoE. OBJECTIVE: We investigated regulation of epithelial LOX expression as a novel biomarker and functional effector of fibrostenotic disease conditions associated with EoE. METHODS: LOX expression was analyzed by using RNA-sequencing, PCR assays, and immunostaining in patients with EoE; cytokine-stimulated esophageal 3-dimensional organoids; and fibroblast-epithelial cell coculture, the latter coupled with fluorescence-activated cell sorting. RESULTS: Gene ontology and pathway analyses linked TNF-α and LOX expression in patients with EoE, which was validated in independent sets of patients with fibrostenotic conditions. TNF-α-mediated epithelial LOX upregulation was recapitulated in 3-dimensional organoids and coculture experiments. We find that fibroblast-derived TNF-α stimulates epithelial LOX expression through activation of nuclear factor κB and TGF-β-mediated signaling. In patients receiver operating characteristic analyses suggested that LOX upregulation indicates disease complications and fibrostenotic conditions in patients with EoE. CONCLUSIONS: There is a novel positive feedback mechanism in epithelial LOX induction through fibroblast-derived TNF-α secretion. Esophageal epithelial LOX might have a role in the development of fibrosis with substantial translational implications.
PubMed ID: 30578874
MeSH Terms: Adolescent; Adult; Aged; Biomarkers/metabolism*; Cells, Cultured; Child; Child, Preschool; Coculture Techniques; Constriction, Pathologic; Eosinophilic Esophagitis/diagnosis; Eosinophilic Esophagitis/genetics*; Epithelial Cells/physiology*; Esophagus/pathology*; Female; Fibroblasts/physiology*; Fibrosis; Gene Ontology; Humans; Infant; Male; Middle Aged; Protein-Lysine 6-Oxidase/genetics*; Protein-Lysine 6-Oxidase/metabolism; Tumor Necrosis Factor-alpha/metabolism*; Up-Regulation; Young Adult